7-nitro-1h-1, 5-benzodiazepine-2,4-(3h,5h)-diones

ABSTRACT

Compounds of the formula   WHEREIN R1 is hydrogen, straight or branched alkyl of one to four carbon atoms, hydroxy-(alkyl of one to four carbon atoms), methoxy(alkyl of one to four carbon atoms), acetoxy-(alkyl of one to four carbon atoms), cyclopropyl-methyl, cyclohexyl or allyl, and R2 is hydrogen, phenyl, o-halo-phenyl, o-trifluoromethyl-phenyl, o-nitro-phenyl, o-cyano-phenyl or pyridyl, PROVIDED, HOWEVER, THAT R1 and R2 are other than both hydrogen at the same time; the compounds are useful as psychosedatives and anticonvulsives.

United States Patent Weber et a].

July 18, 1972 Buchi et 2],, Helv. Chim Acta" 7-NITRO-1H- lS-BENZODIAZEPINE- 2,4-(3H,5H)-DIONES Inventors: Karl-Heinz Weber,Gau-Aigesheim; Adolf Bauer; Herbert Men, both of lngelheim. Rhine: KlausMinck. Gau-Algesheim, all of Germany Assignee: Boehrlnger IngelhelmGmbH, lngelheim, Rhine. Germany Filed: Feb. 1, I971 Appl. No.: 112,070

Foreign Application Priority Data Feb. 13. I970 Germany ..P 20 06 601.7

U.S. Cl ..260/239.3 8, 424/244, 424/263 Int. Cl. ..C07d 53/04 Field ofSearch ..260/239.3 8

References Cited OTHER PUBLICATIONS Vol. 39, pp. 957- 964 PrimaryExaminer-Henry R. Jiles Assistant ExaminerRobert T. BondAttorney-Hammond & Littell [57] ABSTRACT Compounds of the formula IliLMUIO i \C Us (My wherein l0 Claim, No lh'awings 7-NITRO-lH-l5-BENZODlAZEPINE-2,4-(3ll,5ll)-DIONES This invention relates to novel7-nitro-ll-ll ,5- benzodiazepine-2,4-( 3H,5H )-diones, as well as to amethod of preparing these compounds.

More particularly, the present invention relates to a novel class ofcompounds represented by the formula (I) wherein R, is hydrogen,straight or branched alkyl of one to four car bon atoms, hydroxy-(alkylof one to four carbon atoms), methoxy-(alkyl of one to four carbonatoms), acetoxy- (alkyl of one to four carbon atoms),cyclopropyl-methyl, cyclohexyl or allyl, and R, is hydrogen, phenyl,ohalo-phenyl, o-trifluoromethylphenyl, o-nitro-phenyl, ocyano-phenyl orpyridyl, provided, however, that R and R are other than both hydrogen atthe same time.

The compounds of the formula I above may be prepared by oxidizing abenzodiazepinone of the formula wherein R, and R, have the same meaningsas in formula I, with a strong oxidizing agent in the presence of aninert organic solvent.

A mixture of chromic acid and sulfuric acid is preferably used as theoxidizing agent, but potassium pennanganate or activated manganesedioxide may also be successfully employed.

For the oxidation with chromic acid/sulfuric acid or potassiumpermanganate, suitable inert organic solvents are particularly thosewhich are water-miscible and do not themselves undergo oxidation underthe prevailing reaction conditions, such as acetone, methyl ethylketone, glacial acetic acid, dioxane, tetrahydrofuran or mixtures of anytwo or more of these.

For the oxidation with activated manganese dioxide, not only thesolvents mentioned in the preceding paragraph, but also ethyl acetate,diethyl ether, methylene chloride or chloroform may be employed.

The optimum oxidation reaction temperature depends largely upon theparticular starting compound which is used, and generally varies betweenC and the boiling point of the selected solvent medium.

For the preparation of a compound of the formula I wherein R, ishydroxy-alkyl, it is advantageous to start from a correspondingl-acylallryl-2,3,4,5-tetrahydroll-ll ,5- benzodiazepin-Mme and to splitoff the acyl group by conventional methods subsequent to the oxidation.

A compound of the formula I wherein R, is hydrogen may, if desired, besubsequently alltylated in conventional manner.

The above-described oxidation reaction proceeds rapidly and smoothly andwith high yields of the desired end products; some of the startingcompounds of the formula can even be oxidized into the corresponding endproducts of the formula I in a few minutes at room temperature. Thisfact is unobvioul and surprising. Thus, it is well known that2,3-dihydro-L4- benzodiazepines can be oxidized into the corresponding2,3- dihydro-l,4-benzodiazepin-2-ones [see RJ. Freyer et al., J. Org.Chem. 30, 1308 et seq. (I965) but the yields are very poor; forinstance, the yield of 7-nitro-5-phenyl-2,3-dihydro-2H-l,4-benzodiaaepin-2-one from 7-nitro-S-phenyl-2,3-

dihydro-l ,4-ben1odiazepine is only 2.4 percent. On the other hand, itis also well known that l,5-benz0diaze-pines are extremely sensitive tohydrolysis and readily undergo ring cleavage or ring condensation intoimidazoles under acid conditions [see J.A.C.S. 66, I810 I910)Consequently, the expectation would necessarily have been that oxidationin a strong acid medium would also alter the ring structure of L5-benaodiazepin-Zones in the indicated sense andlor produce poor yields.We have unexpectedly discovered that this is not the case.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood, however, that the invention is not limited solelyto the particular examples given below.

EXAMPLE 1 7-Nitro-S-phenyl-l H- l ,$-benzodiazepin-2,4-( I'd-L5H )-dioneSixty-five gm (0.23 mol) of 7-nitro-5-phenyl-23,4,5-tetrahydro-iH-l,5-benaodiazepin-4-one (m.p. 24l C) were dissolved in2,000 ml of acetone, and then 120 ml of an oxidizing solution, preparedfrom 40 gm (30,, 38 ml H,S0,and I50 ml l-l,0, were added dropwise over aperiod of 15 minutes, whereby the internal temperature of the mixedsolution rose. After all of the oxidizing solution had been added, thereaction mixture was stirred for 20 minutes, and the liquid phase wasdecanted from the precipitated chromium salts and concentrated to about300 ml by evaporation. The concentrated solution was poured into 500 mlof water, and the aqueous mixture was briefly brought to the boilingpoint and was then placed on an ice bath to allow the reaction productto crystallize out. 63.5 gm (92 percent of theory) of the compound ofthe formula having a melting point of 272"-274C (recrystallized fromacetonitrile) were obtained.

EXAMPLE 2 Using a procedure analogous to that described in Example 1,27.6 gm (88 percent of theory) of l-methyl-5-phenyl-7- nitro- 1 PH,5-benzodiazepine-2,4-( 3H,5H )-dione, m.p. l78-l 80C, of the formulawere obtained from 29.7 gm (0.] mol) of l-methyl-5-phenyl-7 -nitro-lH-2,3,4,5-tetrahydrol ,5.-benzodiazepin-4-one (m.p. l23-l 25C).

EXAMPLE 3 Using a procedure analogous to that described in Example 1,29.4 gm percent of theory) ofl-ethyl-S-phenyl-l-nitroll-l-l,$-benzodiaaepine-2,4-(3H,$H}-dione, m.p.257-2$9C, were obtained from 3l.l gm (0.l mol) of l-ethyl-5phenyl-7-nitrol H-2,3 ,4,5-tetrahydrol ,S-benzodiazepin-4-one m .p. l60-l62C).

EXAMPLE 4 Using a procedure analogous to that described in Example I,28.0 gm (82 percent of theory) of l-isopropyl-S-phenyl-7- nitrol H- l,5-benzodiazepine 2,4-( 3H,5H l-dione, m.p. 2l2-2l3C, were obtained from32.5 gm (0.1 mol) of lisopropyl-S-phenyl-l-nitro-l H-2,3,4,S-tetrahydrol ,5- benzodiazepin-4-one (m.p. l70-l 71C).

EXAMPLE 5 Using a procedure analogous to that described in Example 1,25.4 gm (75 percent of theory) of l-allyl-5-phenyl7-nitrolH-l,S-benzodiazepine-Z,4-(3H,5H)-dione, m.p. 237-239C, of the formula wereobtained from 323 gm (0.] mol) of l-allyl-5-phenyl-7-nitrolH-2,3,4,5-tetrahydro-1,5-benzodiazepin-4-one (m.p. l26-l27C).

EXAMPLE 6 EXAMPLE 7 l-Methyl-7-nitro-5-phenyl-l H- l,5-benzodiazepine-2A- (3H,5H)-dione Forty gm (0.13 mol) of5-phenyl-7-nitro-lH-l,5- benzodiazepine-2,4-(3H,5H)-dione were suspendedin 600 ml of tetrahydrofuran and caused to go into solution by additionof 6.4 gm of an aqueous 50 percent sodium hydride suspension.Thereafter, 8.5 ml of methyl iodide were added to the solution, themixture was stirred for l hour at 45C, then an additional 8.5 ml ofmethyl iodide were added, and the mixture was again stirred for 1 hour.Subsequently, a few drops of glacial acetic acid were added to thereaction solution which was then evaporated, the residue was taken up inmethylene chloride, the resulting solution was washed with water andthen dried the methylene chloride was evaporated, and the residue wasrecrystallized from methylene chloride/diisopropyl ether. Thirty-five gmof l-methyl-7-nitro- S-phenyl-lH-l,5-benzodiazepine-2,4-(3H,5H)-dione,m.p. l79-l8 lC, were obtained.

EXAMPLE 8 l-(B-Hydroxy-ethyl )-7-nitro-5-phenyll H- l ,5-benzodiazepine-2,4-(3H,5H)-dione Twenty gm (0.07 mol) of7-nitro-5-phenyll i i-1,5- benzodiazepine-2,4-(3H,5H)-dione weresuspended in 600 ml of methanol; 10 ml of water, 1 ml of Triton B (35percent solution of benzyl trimethylammonium hydroxide in methanol) and50 ml of ethyleneoxide were added to the suspension, and the mixture wasstirred at room temperature until a clear solution was fonned, whichoccurred after about 50 hours. Thereafter, the solution was evaporatedto dryness, the residue was taken up in methylene chloride, theresulting solution was extracted several times with water, the organicphase was dried and then evaporated, and the residue was recrystallizedfrom ethanol. Eleven gm of the compound of the formula having a meltingpoint of l87-l 88C were obtained.

EXAMPLE 9 Using a procedure analogous to that described in Example 1,S-(o-ehloro-phenyl)-7-nitro-lH-l ,5-benaodiazepine2,4-(3 H,5H l-dione,mp. 250-252C, of the formula was obtained fromS-(o-chloro-phenyl)-7-nitr0-l-2,3,4,5- tetrahydro-l,5-benzodiazepin-4-one.

EXAMPLE 10 Using a procedure analogous to that described in Example 1,l-n-propyI-5-phenyl-7-nitrol H- l ,5-benzodia2e-pine-2,4- (3H,SH)-dione,m.p. 23924lC, was obtained from l-npropyI-5-phenyl-7-nitrolH-2,3,4,5-tetrahydro-l ,5- benzodiazepin-t-one.

EXAMPLE I I Using a procedure analogous to that described in Example 1,S-(o-fluoro-phenyl )-7-nitro-l H- l ,S-benzodiazepine-2,4-( 3 H,5H)-dione, m.p. 260-263C, of the formula was obtained fromS-(o-fluoro-phenyl)-7-nitro-lH-2,3,4,5- tetrahydro-l,5-benzodiazepin-4-one.

EXAMPLE 12 Using a procedure analogous to that described in Examplel-methyl-5-(o-fluoro-phenyl)-7-nitro-1H l ,5-benzodiazepine-2,4-(3H,5H)-dione, m.p. l l3-l l5C (decomp;recrystallized from methanol with one mol of methanol ofcrystallization), was obtained from l-methyl-S- (o-fluoro-phenyl)-7-nitrol H-2,3,4,5-tetrahydrol ,5- benzodiazepin-4-one.

EXAMPLE 13 Using a procedure analogous to that described in Example I,l-n-butyl-5-(o-fluoro-phenyl)-7-nitro-l H- l ,5-benzodiazepine-2,4-(3H,5H)-dione, m.p. l64-l66"C, was obtained froml-n-butyl-5'(o-fluoro-phenyl)-7-nitrol H- 2,3,4,S-tetrahydro-l,S-benzodiazepintone.

EXAMPLE 14 Using a procedure analogous to that described in Example 1,5-(o-nitro-phenyl )-7-nitro-l H-l ,S-benzodiazepine-2,4-( 3 H,5H)-dione,m.p. 285286C, of the formula was obtained fromS-(o-nitro-phenyl)-7-nitro-lH-2,3,4,5- tetrahydro-I,5-benz0diazepin-4-one.

EXAMPLE EXAMPLE l6 Using a procedure analogous to that described inExample I, l-ethyl-S-(o-nitro-phenyl )7-nitrol H- I ,5-benzo-diazepine-2,4-(3H,5H)-dione, m.p. 226228C, was obtained from I-ethyl-S-(o-nitro-phenyl )-7-nitrol H-2,3,4,S-tetrahydrol ,5-benzodiazepin-4-one.

EXAMPLE 1';

Using a procedure analogous to that described in Example 1,l-isopropyl-S -(o-nitro-phenyl )-7-nitrol H- l ,5-benzodiazepine-2,4-(3H,5H)-dione, m.p. 240242C, was obtained froml-isopropyl-5-(o-nitro-phenyl)-7-nitro-1H- 2,3 ,4,5-tetrahydrol,5-benzodiazepin-4-one.

EXAMPLE l8 was obtained from 5-(o-trifluoromethyl-phenyl)-7-nitro-1H-2,3 ,4,5-tetrahydrol ,S-benzodiazepinJ-one.

EXAMPLE 19 Using a procedure analogous to that described in Example I,l-methyl-5'( 2 '-pyridyl)-7-nitro-1H-l ,S-benzodiazepine-2,4-(3H,5H)-dione, m.p. l76l 77C, of the formula 6 was obtained froml-methyl-5-(2'-pyridyl)-7-nitro-IH- 2,3,4,5-tetrahydro-l,S-benzodiazepin-d-one.

EXAMPLEZO Using a procedure analogous to that described in Example 1,l-methyl-7-nitro-l H- l ,$-benzodiazepine-2,4-( 3H,5 H dione, m.p.230-23 IC, ofthe formula was obtained froml-methyl-7-nitro-lH-2,3,4,5-tetrahydrol,5-benzodiazepin-4-one.

EXAMPLE 2| Using a procedure analogous to that described in Example Il-(cyclopropyl-methyl)-5-phenyl-7-nitro-l H- l ,5-benzodiazepine-2,4-(3H,5H)-dione, m.p. 28028lC, of the formula wasobtained from I-(cyclopropyl-methyl)-5-phenyl-7-nitrolH-2,3,4,5-tetrahydro-l ,5 -benzodiazepin-4-one.

The compounds according to the present invention, that is, thoseembraced by formula 1 above, have useful pharmacodynamic properties.More particularly, the compounds of the instant invention exhibit veryeffective psychosedative (tranquilizing) and anticonvulsive activitiesin wann-blooded animals, such as mice, rats, minks, cats, dogs.Particularly effective are those compounds of the formula I wherein R ishydrogen, methyl, fl-hydroxy-ethyl or allyl, and R, is phenyl,o-substituted phenyl or a-pyridyl.

For pharmaceutical purposes the compounds according to the presentinvention are administered to warm-blooded animals perorally orparenterally as active ingredients in customary dosage unitcompositions, that is, compositions in dosage unit form consistingessentially of an inert pharmaceutical carrier and one effective dosageunit of the active ingredient, such as tablets, coated pills, capsules,wafers, powders, solutions, suspensions, emulsions, syrups,suppositories and the like. One effective dosage unit of the compoundsaccording to the present invention is from 0.0166 to 0.84 mgm/kg bodyweight, preferably 0.083 to 0.42 mgm/ltg body weight, and the daily doserate is from 0.166 to 2.5 mgm/kg 5 body weight.

The following examples illustrate a few dosage unit compositionscomprising a compound of the present invention as an active ingredientand represent the best modes contemplated of putting the invention intopractical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 22 Coated pills The pill core composition is compounded from thefollowing ingredients:

l-Methyl-phenyl-7-nitro l H-l ,S-benzodiazepine- 2,4-(3H,5H )dione 5.0parts Lactose 28.5 parts Corn starch l5.0 parts Gelatin l .0 partsMagnesium stearate 0.5 parts Total 50.0 parts Preparation:

The benzodiazepine compound is intimately admixed with the lactose andthe corn starch, the mixture is moistened with an aqueous 10 percentsolution of the gelatin, and the moist mass is granulated through a 1mm-mesh screen, dried at 40C and again passed through the screen. Theresulting dry granulate is admixed with the magnesium stearate, and themixture is compressed into 50 mgm-pill cores which are then coated witha thin shell consisting e entially of a mixture of talcum and sugar, andthe coated pills are polished with beeswax. Each pill contains 5.0 mgmof the benzodiazepine compound and is an oral dosage unit compositionwith effective tranquilizing and anticonvulsive action.

EXAMPLE 23 Tablets The tablet composition is compounded from thefollowing ingredients:

5-Phenyl-7-nitro-li-l-l .5- benzodiazepine-2,4-

(3H,SH )-di0ne 3.0 parts Lactose 500 parts Corn starch 32.0 partsSoluble starch 4.0 parts Magnesium stearate l .0 parts Total 90.0 partsEXAMPLE 24 Suppositories The suppository composition is compounded fromthe following ingredients:

l-Allyl-iphenylJ-nitrol H- l ,Sbenmdiazepine-2,4-( 3H ,5H )-dione 5.0parts Cocoa butter l695.0 parts Total l700.0 parts Preparation:

The finely pulverized benaodiazepine compound is stirred with the aid ofan immersion homogenieer into the cocoa butter which has previously beenmelted and cooled to 40C, and 1,700 mgm-portions of the mixture arepoured at 35C into cooled suppository molds. Each suppository contains5.0 mgm of the benzodiazepine compound and is a rectal dosage unitcomposition with effective tranquilizing and anticonvulsive action.

EXAMPLE 25 Hypodermic solution The solution is compounded from thefollowing ingredients:

l-(B-Hydroxy-ethyl)-5-phenyl-7- nitrol H- l ,5-benzodiazepine-2,4-

(3",5Hl-dione 2.0 parts Sodium chloride 18.0 parts Distilled waterq.s.ad 2000.0 parts by vol.

Preparation:

The benzodiazepine compound and the sodium chloride are dissolved in asufficient amount of distilled water, and the solution is diluted withadditional distilled water to the indicated volume, filtered until freefrom suspended particles, and filled under aseptic conditions into 2cc-ampules which are finally sterilized for 20 minutes at I20C and thensealed. The solution in each ampule contains 2 mgm of the benzodiazepinecompound and is an injectable dosage unit composition with effectivetranquilizing and anticonvulsive action.

Analogous results are obtained when any one of the otherbenzodiazepine-diones embraced by formula I is substituted for theparticular benzodiazepine-dione in Examples 22 through 25. Likewise, theamount of active ingredient in these illustrative examples may be variedto achieve the dosage unit range set forth above, and the amounts andnature of the inert pharmaceutical carrier ingredients may be varied tomeet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily ap parent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. A compound of the formula R.- wherein R, is hydrogen, alkyl of one tofour carbon atoms, hydroxy(alky| of one to four carbon atoms),mcthoxy-(alkyl of one to four carbon atoms), acetoxy-(alkyl of one tofour carbon atoms), cyclo-propyl-methyl, cyclohesyl or allyl, and

R is hydrogen, phenyl, o-halo-phenyl, o-trifluoro-methylphenyl,o-nitro-phenyl, o-cyano-phenyl or pyridyl, provided, however, that R,and R are other than both hydrogen at the same time.

2. A compound according to claim 1, wherein R, is hydrogen, alkyl of oneto four carbon atoms, hydroxy-ethyl, allyl or cyclopropyl-methyl, and

R is hydrogen, phenyl, o-chloro-phenyl, o-fluorophenyl, o-

nitro-phenyl, o-trifluoromethyl-phenyl or a-pyridyl, pro vided, however,that R, and R, are other than both hydrogen at the same time.

3. A compound according to claim 2, which is l-methyl-S- phenyl-l-nitrolH- l ,5-benzodiazepine-2,4-( 3H,SH )-dione.

4. A compound according to claim I, wherein R, is hydrogen, methyl,B-hydroxy-ethyl or allyl, and R, is phenyl, o-chloro-phenyl,o-fluoro-phenyl, o-nitro-phenyl, otrifluoromethyl-phenyl or a-pyn'dyl.

5. A compound according to claim 2, which is $-phenyl-7- nitrol H-l,$-benzodiazepine-2,4-( 3H,SH i-dione.

6. A compound according to claim 2, which is l-(B-hydroxy-ethyl)-5-phenyl 7-nitrol H ,l ,S-benzodiazepine-2,4-( 3H,5 H)-dione.

7. A compound according to claim 2, which is l-methyl-S-(o-fluoro-phenyl )-7-nitrol "-1 ,5-benzodiazepine-2,4- (3H,5H)-dione.

8. A compound according to claim 2, which is l-rnethyl-S-(2'-pyridyl)-7-nitro-lH-l ,S-benzodiazepine-ZAA3H,5l-I)- dione.

9. The process of preparing a compound according to claim 1, whichconsists of oxidizing a compound of the formula iii 9 10 wherein R andR, have the same meanings as in claim I, with 10, The process accordingto claim 9, wherein said strong a strong oxidizing agent in the presenceof an inert, non-oxoxidizing agent is selected from the group consistingof potasidizable organic solvent at a temperature between 20C and 8ill!"permanganate. filmed fl g e dioxide and mix the boiling point of saidsolvent, and recovering the oxidation l r s fchromic acid and sulfuricacid.

product. 5 a e e e e mg UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3578,033 Mu Dated July 18, 1972 Inventor)KARL-HEINZ WEBER, ADOLF BAUER, HERBERT MERZ -WMIME It is certified thaterror appears in the above-identified patent and that said LettersPatent: are hereby corrected as shown below:

601. 2, line 38 correct the formula to, read "I 0' t I N CH OQN 1 qcCol. u, .line 25 correct "1-2',3, +",5-" to read --1H-2,3,4,5-

Signed and sealed this 13th day of March 1973 (SEAL) Attest:

ROBERT GOTTSCHALK EDWARD M PLETCHER,JR.

Commissioner of Patents Attesting Officer

2. A compound according to claim 1, wherein R1 is hydrogen, alkyl of oneto four carbon atoms, hydroxy-ethyl, allyl or cyclopropyl-methyl, and R2is hydrogen, phenyl, o-chloro-phenyl, o-fluoro-phenyl, o-nitro-phenyl,o-trifluoromethyl-phenyl or Alpha -pyridyl, provided, however, that R1and R2 are other than both hydrogen at the same time.
 3. A compoundaccording to claim 2, which is1-methyl-5-phenyl-7-nitro-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
 4. Acompound according to claim 1, wherein R1 is hydrogen, methyl, Beta-hydroxy-ethyl or allyl, and R2 is phenyl, o-chloro-phenyl,o-fluoro-phenyl, o-nitro-phenyl, o-trifluoromethyl-phenyl or Alpha-pyridyl.
 5. A compound according to claim 2, which is5-phenyl-7-nitro-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
 6. A compoundaccording to claim 2, which is 1-( Beta-hydroxy-ethyl)-5-phenyl-7-nitro-1H,1,5-benzodiazepine-2,4-(3H,5H)-dione.7. A compound according to claim 2, which is1-methyl-5-(o-fluoro-phenyl)-7-nitro-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
 8. A compound according to claim 2, which is 1-methyl-5-(2''-pyridyl)-7-nitro-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione.
 9. Theprocess of preparing a compound according to claim 1, which consists ofoxidizing a compound of the formula
 10. The process according to claim9, wherein said strong oxidizing agent is selected from the groupconsisting of potassium permanganate, activated manganese dioxide andmixtures of chromic acid and sulfuric acid.